Delivery of drugs has been a major problem for many years, particularly when the compound to be delivered is unstable under the conditions encountered in the gastro-intestinal tract when administered orally to a subject, prior to reaching its targeted location. For example, it is preferable in many cases to administer drugs orally especially in terms of ease of administration, patient compliance, and decreased cost. However, many compounds are ineffective or exhibit low or variable potency when they are administered orally. Presumably this is because the drugs are unstable under conditions in the digestive tract or because they are inefficiently absorbed. For biologic products, in particular peptides and proteins, the acidic environment in the stomach is detrimental to maintain function as most proteins are degraded readily.
Isolated biological substances, including, certain proteins and peptides can readily and completely lose functional activity, for example, by taking them out of −20° C. storage once. Other isolated proteins and peptides undergo significant degradation when stored at 4° C., without the addition of protease inhibitors. Most mammalian proteins and peptides degrade at a temperature greater than 43° C. It has been well established that at 55° C., most proteins undergo complete denaturation in about 1-2 hours. In some cases, complete denaturation and destabilization of an isolated protein also occurs at room temperature.
Due to the problems associated with oral drug delivery of drugs and in particular, biologically-derived products, drug delivery to the lungs has been explored. For example, drugs delivered to the lungs are designed to have an effect on the tissue of the lungs, for example, vasodilators, surfactants, chemotherapeutic agents or vaccines for flu or other respiratory illnesses. Drug formulations for treating pulmonary diseases such as asthma are available by several methods, including, using nebulizers such as treatment with PULMOZYME®, using metered-dose inhalers such as SYMBICORT®, and dry powder inhalers such as ADVAIR DISKUS®, PULMICORT FLEXAHER®. Other drugs, including nucleotide drugs, have been delivered to the lungs because they represent a tissue particularly appropriate for treatment, for example, for genetic therapy in cystic fibrosis, where retroviral vectors expressing an effective adenosine deaminase are administered to the lungs.
Currently, formulations for treating systemic disease using biologic products are available primarily through injectable compositions. Dry powder compositions for pulmonary inhalation and systemic delivery of insulin have been used including EXUBERA®, and AFREZZA® in clinical trials. There is the desire, however, to improve the shelf-life at room temperature for dry powder compositions, especially those comprising a biologic molecule, including peptides and nucleic acids, to further prolonged their life, facilitate their storage and delivery prior to patient use, particularly if refrigeration is not available.
For example, according to the World Health Organization, 800 women die every day from pregnancy or childbirth-related complications. Among the major causes of death is severe bleeding (post-partum hemorrhage) that can be prevented by the use of a peptide hormone, oxytocin, a biologic molecule. Commercially available oxytocin compositions are provided as liquid formulations under the trade names PITOCIN® and SYNTOCINON® or as generic oxytocin; the peptide in solution degrades readily at ambient temperature, requires storage below 25° C. prior to use, and is administered only by injection. The preparations of injectable formulations and special storage needed create challenges, which prohibit their use in subtropical and tropical climates where there is a great need, and refrigeration and sterilization are not always readily available.
Accordingly, there is room for improvement in the development of pharmaceutical formulations comprising biologic molecules in particular for pulmonary delivery in the treatment of disease.